Xeno nucleic acids (XNAs) are artificial genetic systems based on sugar-modified nucleotides. Herein, we investigate double-headed nucleotides as a new XNA. A new monomer, AT, is presented, and together with...
Nucleotide monomers that hold two nucleobases each, i.e. double-headed nucleotides, have been shown to form two sets of functional Watson–Crick base pairs when incorporated into dsDNA, and they hereby behave...
Double-headed nucleotides are DNA building blocks that store, in principle, twice as much information as native nucleotides due to the incorporation of an additional functional nucleobase. Herein, we present the development of two new doubleheaded nucleotides, U W and U Z, featuring a methylene-linked 5aza-7-deazaxanthine (Z) and a propynyl-linked pseudouracil (W), respectively, attached to the 2'-position of arabinouridine. These analogs are evaluated in DNA duplexes for their ability to act as dinucleotides, and the base-pairing specificities of the 2'nucleobases are compared to previous analogues. Although an improved discrimination was observed in the context of a cytosine mismatch using U Z , neither of the two new analogs gave rise to increased overall base-pairing fidelity possibly due to the formation of stable wobble pairs. Furthermore, we present an improved synthetic strategy for the preparation of the corresponding diaminopurine analog (U D), in which the key fluoro-to-amino substitution is achieved post-synthetically to avoid the use of doubly protected diaminopurines and complicated deprotections.
Through the use of modified nucleotides,
synthetic nucleic acids
have found several fields of application within biotechnology and
in the pharmaceutical industry. We have previously introduced nucleotides
with an additional functional nucleobase linked to C2′ of arabinonucleotides
(B
X
). These double-headed nucleotides
fit neatly into DNA·DNA duplexes, where they can replace the
corresponding natural dinucleotides and thus condense the molecular
information. Here, we introduce a 2′-deoxy version of the B
X
design with inversion of the C2′
stereochemistry (
d
S
B
X
) with the aim of obtaining
improved RNA recognition. Specifically,
d
S
B
X
analogues with cytosine or isocytosine attached to C2′ of
2′-deoxyuridine (
d
S
U
C
and
d
S
U
iC
) were synthesized and evaluated in duplexes. Whereas the
d
S
B
X
design did not outperform the B
X
design in terms of mimicking dinucleotides
in nucleic acid duplexes, it was able to engage in reverse Watson–Crick
pairing using its 2′-base. This was evident from the ability
of the
d
S
U
C
cytosine to form stable mis-matching
base pairs with opposite cytosines identified as hemiprotonated C·C+ pairs. Furthermore, specific base-pairing with guanine was
only observed for the isocytosine-bearing
d
S
U
iC
monomer. Very stable duplexes were obtained with
d
S
U
C/iC
monomers in each strand indicating that fully modified double-headed
nucleic acid sequences could be based on the
d
S
B
X
design.
Double-headed nucleotides, i. e., nucleotides that hold two nucleobases each, have been shown to be double-functional in DNA duplexes by forming two sets of WatsonÀ Crick base pairs, and thus mimicking dinucleotides. Herein, we present three new double-headed nucleotides, U T + , U A + and U ClU , with the non-natural nucleobases 5-(3-aminopropynyl)uracil (T +), 7-(3aminopropynyl)-7-deazaadenine (A +) and 5-chlorouracil (ClU) attached to the 2'-position of arabinouridine via a methylenelinker. With extended π-systems and amino groups for electro-static interaction with the DNA backbone, incorporation of U T + and U A + increased duplex stability compared to their unmodified predecessors, U T and U A . For U T + , discrimination of mismatches was slightly improved compared to U T , whereas this was not the case for U A + . The U ClU analogue also increased duplex stability compared to U T and provided better mismatch discrimination than both U T and U T + . Thereby it represents the leading bis-uracil double-headed nucleotide analogue.
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